PROJECT SUMMARY/ABSTRACT Pancreatic cancer ranks fourth in cancer related deaths in the United States. It has very poor prognosis. The five year survival rate is only 6%. Approximately 30% of pancreatic cancer patients die with locally destructive pancreatic cancer. Despite a high tendency for metastatic spread, radiotherapy plays an important role in the management of locally advanced unresectable pancreatic cancer. For pancreatic cancer, the radiation dose used in standard practice is suboptimal. The prescribed dose is limited by the radiation intolerance of adjacent normal organs such as small intestine, duodenum, stomach, kidneys and spinal cord. Despite rapid technical development in radiation therapy, the ability of radiation to treat locally advance pancreatic cancer remains limited, primarily due to late gastrointestinal (GI) toxicity. Reducing GI toxicity for pancreatic cancer patients is very challenging, mainly because none of the current imaging techniques have the capability to track the respiration induced motion of the pancreatic tumor itself. Although four dimensional (4D) computed tomography (CT) can be used to assess organ motion, poor soft tissue contrast makes it of limited value for the pancreas. Magnetic resonance imaging (MRI) has excellent soft tissue contrast and is ideal for imaging tissues within the abdomen. However, without a practical and robust triggering system, its potential in 4D imaging has been tremendously limited. Currently, only balanced steady-state free procession (SSFP) and spoiled SSFP sequences are compatible with existing 4DMRI, and both sequences suffer from low tumor to tissue contrast. In this work, we will develop a novel respiration-amplitude-triggered 4DMRI technique which utilizes multiple triggers at pre-selected respiratory amplitudes to guide image acquisition. Our innovative approach will be able to 1) accommodate a variety of sequences, e.g. T2 weighting or diffusion weighting, to enhance tumor to tissue contrast, and 2) achieve excellent spatial and temporal resolution for motion tracking and radiation therapy treatment planning. We will evaluate the proposed 4DMRI technique on locally advanced pancreatic cancer patients. Comparisons will be made between 4DMRI and 4DCT on tumor delineation, tumor motion, as well as inter- and intra-observer variability. In addition, we will compare treatment plans generated using the same margin from two sets of contours based on 4DMRI and 4DCT to see if dose distributions from the two treatment plans differ in a clinical relevant way. We will also compare treatment plans generated from the same set of contours based on 4DMRI but with different treatment margins to determine if reducing the margin will result in clinical relevant improvement. If our method proves to be effective, we will be able to accurately track the movement of the pancreatic tumor. With reduced uncertainty in tumor location, shape and motion, we will be able to provide more conformal treatments, reducing radiation dose to normal tissues and thus the GI toxicity rate.